Download Long-acting inhaled bronchodilators in COPD: how many drugs do we need? EDITORIAL

Eur Respir J 2005; 26: 190–191
DOI: 10.1183/09031936.05.00054905
CopyrightßERS Journals Ltd 2005
EDITORIAL
Long-acting inhaled bronchodilators in COPD:
how many drugs do we need?
P.M.A. Calverley
ronchodilators remain the mainstay of chronic obstructive pulmonary disease (COPD) management and are
recommended for the treatment of symptomatic
patients at all stages of this disease [1]. For many years studies
of these drugs focussed on changes in forced expiratory
volume in one second (FEV1) or, occasionally, forced vital or
slow vital capacity, believing that these robust and reproducible end-points were a legitimate surrogate for the changes in
symptomatology, which were the real interest of patients and
clinicians alike. By the 1990s, this comfortable assumption had
been challenged when it became clear that individual
improvement in exercise capacity and breathlessness were
not closely related to changes in the magnitude of these
spirometric indices [2]. This stimulated research into the
determinants of exercise performance and dyspnoea in
COPD, and why spirometry was of so little help in predicting
symptomatic improvement. A range of mechanisms have been
identified and have recently been reviewed [3]. Principal
among these is the change in end-expiratory lung volume
(EELV) during exercise in COPD patients. When healthy
subjects exercise, EELV is reduced helping to keep the
operating lung volumes on the steeper part of the pressurevolume relationship. COPD patients with tidal expiratory flow
limitation must either allow EELV to rise [4], or try to
overcome flow limitation at their initial lung volume an
unsatisfactory strategy which limits exercise performance [5].
Most patients with more severe disease adopt for the former
approach which allows them to exercise longer, but at the cost
of increasing difficulty in breathing as EELV approaches total
lung capacity [6].
B
Several studies have examined exercise performance in light of
this improved mechanistic understanding. Studies with the
shorter acting anticholinergic drug ipratropium confirmed that
the degree of spirometric change was unrelated to any
improvement in exercise performance [7], but that increases in
inspiratory capacity during exercise did identify individuals
who could exercise for longer. Further data with both
tiotropium and salmeterol [6, 8] have shown that these
bronchodilator drugs lower resting EELV which creates more
‘‘room’’ within the thorax to accommodate the volume change
that exercise produces. At any time during exercise the degree of
breathlessness is less after the bronchodilator drug, although at
end-exercise when the inspiratory reserve volume approaches
500 mL a rapid increase in self-reported breathlessness occurs.
CORRESPONDENCE: P.M.A. Calverley, The University Hospital Aintree, Liverpool, L9 7AL, UK. Fax:
44 1515295888. E-mail: [email protected]
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This reflects the substantial neuro-mechanical dissociation
which occurs when EELV approaches total lung capacity.
Data with salmeterol suggests that the main effect of this drug
is to delay the time taken to reach this point [6], although other
subtler mechanisms have been proposed [9].
Thus, changes in operating lung volume explain why
bronchodilators make people less breathless and why small
changes in mean FEV1, measured as an average change in
groups of COPD patients, rather than individuals, can be
accompanied by important clinical benefits. However, detailed
mechanistic studies of this type are too complex to answer all
our questions about how and when to use bronchodilator
drugs, and in many circumstances we are still reliant on
detecting small changes in spirometry to guide clinical
practice. This is especially true when we determine the
duration of action of drugs and whether combining drugs is
better than using either one alone.
Although differences in the pharmacology of individual
bronchodilators have been a topic of much discussion, the
most useful practical development has been to prolong their
duration of action. Despite differences in dissociation times for
different muscarinic receptor subtypes, tiotropium improves
exercise performance in COPD patients in a similar way to
short-acting anticholinergic drugs [7, 8]. However, tiotropium
can be taken q.d. and produces improvements in spirometry for
o24 h, including the overnight period [10]. This sustained
action maintains airway patency, which previously we have
argued to be desirable in COPD [11]. This is the most likely
reason for the superior clinical performance of this agent
compared with its short-acting counterparts [12].
Although tiotropium is a very effective anticholinergic drug, it is
unlikely that the current dosing regime is on the flat part of the
dose-response relationship [13], with the dose of 18 mg q.d. being
chosen to represent a reasonable compromise between clinical
efficacy and the risk of systemic absorption and toxicity. Indeed,
combining anticholinergic and b-agonist in high doses can still
produce significant improvements in lung function and lung
volume irrespective of the presence of expiratory flow limitation
[14]. This has been the basis of the widely used regular shortacting combination drugs in COPD [15]. Inevitably, clinicians
would also like to know whether there is any benefit in
combining long-acting inhaled drugs as well and in this issue of
the European Respiratory Journal, a helpful study is reported
which begins to address this complex problem [16].
In the present issue, VAN NOORD et al. [16] compared tiotropium
q.d., the long-acting inhaled b-agonist formoterol b.i.d., and the
EUROPEAN RESPIRATORY JOURNAL
P.M.A. CALVERLEY
combination of tiotropium q.d. and formoterol q.d. in a
randomised placebo-controlled crossover trial in 71 patients
with stable COPD (mean FEV1 37% predicted). Patients took
each treatment for 6 weeks at the end of which spirometry was
recorded 17 times over the subsequent 24 h to identify early
and more sustained changes in lung function after each drug.
Regular peak flow recordings were made and rescue medication use was noted, but other measurements such as
inspiratory capacity were not added to what was already a
demanding protocol.
Several points emerged clearly. The patients enrolled were
very similar to those reported in previous studies of tiotropium
[12, 17–19] and, as anticipated, there was a significant
improvement in mean trough FEV1 of ,100 mL after this
drug. This is comparable with other studies and was
significantly greater than that after formoterol (b.i.d.). There
was further significant improvement in spirometry over the
first 12 h after the two drugs were taken together. As noted
previously [10], the diurnal variation in lung function persists
despite inhaled tiotropium therapy and there was no evidence
of any residual effect from the morning dose of formoterol over
the second half of the day. Similar changes were seen in peak
expiratory flow and drug combination was well tolerated.
There was a greater reduction in the daytime use of ‘‘rescue’’
salbutamol during treatment with the combination compared
with the individual components, but this was the only
clinically important comparator included in this study.
The present data are interesting although largely limited to
spirometric outcomes and represent an unusual dosing regime
for clinical purposes. The crossover design of the study is a
considerable strength, as is the detailed time course data after
sustained dosing with these drugs. There is clear evidence of
additional benefit when the drugs are combined and this is lost
as the formoterol effect wears off. There is currently considerable interest in developing q.d. inhaled therapy that combines
the undoubted benefits of tiotropium with an equally longacting b-agonist. Formoterol q.d. does not meet this requirement, but b.i.d. therapy would appear to be worth exploring in
studies where relevant clinical end-points are evaluated.
The persistent increase in airflow obstruction that characterises
chronic obstructive pulmonary disease is best addressed by
improving lung function throughout the 24-h day and
certainly during the period when patients are awake and most
active. The new data from VAN NOORD et al. [16] suggests that,
to achieve this goal, we can do more than we currently are. In
this setting, modest improvements spirometrically often
indicate larger functionally important changes. The challenge
for the future will be to establish whether the clinical benefit
produced by combining these drug classes merits the
additional expense and potential inconvenience of adding
another inhaler to an already complex treatment regime.
COMBINING BRONCHODILATORS IN COPD
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